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Low Gamma-GT Familial Intrahepatic Cholestasis

National Organization for Rare Disorders, Inc.

ImportantIt is possible that the main title of the report Low Gamma-GT Familial Intrahepatic Cholestasis is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

benign recurrent intrahepatic cholestasis types 1 and 2

BRIC1

BRIC2

progressive familial intrahepatic cholestasis types 1 and 2

PFIC1

PFIC2

Disorder Subdivisions

BRIC type 1; mild FIC1 deficiency; mild ATP8B1 disease

BRIC type 2; mild BSEP deficiency; mild ABCB11 disease

Byler disease

Byler syndrome

Greenland childhood cholestasis

PFIC type 2; severe BSEP deficiency; severe ABCB11 disease

PFIC type 1; severe FIC1 deficiency; severe ATP8B1 disease

General Discussion

Low gamma-GT (GGT) familial intrahepatic cholestasis refers to a spectrum of disease, ranging from mild to severe cases. This spectrum of disease predominantly affects the liver. A variety of disorders leads to low GGT familial intrahepatic cholestasis. Children with defects in bile acid synthesis or conjugation, children with abnormalities of contact between liver cells, children with abnormalities of cell organization manifest as arthrogryposis-renal dysfunction-cholestasis syndrome, and children with "neonatal hemochromatosis" all may have low GGT familial intrahepatic cholestasis. These disorders are not covered in this report.

This report covers the two severe and two mild forms of low GGT familial intrahepatic cholestasis that have been generally recognized, although researchers have begun to identify cases that fall in between these two extremes. The severe forms are known as progressive familial intrahepatic cholestasis (PFIC) 1 and 2 and the two milder forms are known as benign recurrent intrahepatic cholestasis (BRIC) 1 and 2. PFIC and BRIC thus lie at different ends of a spectrum. Some persons with low GGT familial intrahepatic cholestasis cannot be shown to have any of the disorders mentioned in this paragraph or in the preceding paragraph. The search continues for causes for these persons' illness or illnesses.

The main symptom of this spectrum of disease is interruption or suppression of the flow of bile from the liver (cholestasis). Cholestasis in these disorders occurs due to defects within the liver (intrahepatic) rather than within the bile ducts outside the liver (extrahepatic). Features of cholestasis may include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, growth deficiency, easy bleeding, rickets, and persistent, severe itchiness (pruritus). In many cases, symptoms or signs are present at birth or during the newborn period. The more severe forms of these disorders eventually progress to cause life-threatening complications such as scarring of the liver (cirrhosis) and liver failure.

PFIC1 and BRIC1 are caused by mutations in a gene named ATP8B1. ATP8B1 encodes a protein named familial intrahepatic cholestasis 1 (FIC1). PFIC2 and BRIC2 are caused by mutations in a gene named ABCB11. ABCB11 encodes a protein named bile salt export pump (BSEP). All forms of PFIC are inherited as an autosomal recessive trait. Some affected individuals do not have mutations in either of these genes, suggesting that additional, as of yet unidentified, forms of these disorders may exist.

These disorders have normal or low serum levels of an enzyme known as gamma-glutamyltransferase (GGT) and, therefore, may be collectively known as low GGT familial intrahepatic cholestasis. Most children with severe cholestasis have elevated levels of this enzyme, enabling physicians to distinguish these disorders from other causes of cholestasis.

Researchers have also identified a disorder known as PFIC type 3 or multidrug resistance protein 3 (MDR3) deficiency. Although this disorder is often grouped with PFIC1 and PFIC2, it is associated with high levels of GGT enzyme activity and the underlying defects causing this disorder are different. MDR3 deficiency is not covered in this report.

The classification of these disorders is complicated and has continually changed as more about these disorders has become known. The classification and grouping of these disorders may undergo further changes in the future. Both these disorders were called "Byler disease" at one time, until their different genetic basis became clear. Various other names have been used for these disorders such as FIC1 deficiency for PFIC1 and BSEP deficiency for PFIC2, adding to the confusion.

For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders (NORD). A copy of the complete report can be downloaded free from the NORD website for registered users. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational therapies (if available), and references from medical literature. For a full-text version of this topic, go to www.rarediseases.org and click on Rare Disease Database under "Rare Disease Information".

The information provided in this report is not intended for diagnostic purposes. It is provided for informational purposes only. NORD recommends that affected individuals seek the advice or counsel of their own personal physicians.

It is possible that the title of this topic is not the name you selected. Please check the Synonyms listing to find the alternate name(s) and Disorder Subdivision(s) covered by this report

This disease entry is based upon medical information available through the date at the end of the topic. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.

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